LAUSR

Heparanase (HPSE) is an endo-β-D-glucuronidase and the only known enzyme responsible for the cleavage of heparan sulfate (HS) side chains from heparan sulfate proteoglycans (HSPGs). The enzymatic activity of HPSE mediates ECM remodeling, regulates growth factors, and modulates related signaling pathways, thus HPSE has emerged as a novel therapeutic target for various diseases, including most types of cancers. In the last two decades, a number of HPSE inhibitors have been reported by several labs worldwide, with most of them belonging to the heparan sulfate mimics category. So far, few of the small molecule HPSE inhibitors have progressed into clinical trials and none has gained approval by regulatory agencies, leaving a blank in HPSE drug discovery. Here we present the discovery of a novel HPSE small molecule inhibitor by high-throughput screening using an ultrasensitive HPSE enzymatic detecting probe developed in our lab and provide the mechanisms of action behind the small molecule’s HPSE inhibitory activity. By doing a series of molecular dynamics (MD) simulations, we discovered the binding profiles on the derivatives of the lead compound. We summarized the essential structural features of the lead compound to provide insights into the design of future HPSE small molecule inhibitors. Citation Format: Yuzhao Zhang, Meijun Xiong, Zixin Chen, Gustavo Seabra, Jun Liu, Chenglong Li, Lina Cui. Design principle of heparanase inhibitors: A combined in vitro and in silico study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3105.